IPR2025-00808 Declaration of Brian Zeglis
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`––––––––––––––––––
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`––––––––––––––––––
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`Petitioner, GE Healthcare Ltd.,
`Petitioner
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`v.
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`Johns Hopkins University,
`Patent Owner.
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`––––––––––––––––––
`
`Case No. IPR2025-00808
`U.S. Patent No. 11,938,201
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`––––––––––––––––––
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`Declaration of Brian Zeglis, Ph.D.
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. i
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`I.
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`II.
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`Table of Contents
`INTRODUCTION ........................................................................................ 1
`A.
`Background and Qualifications ........................................................ 1
`B.
`Compensation ..................................................................................... 4
`C.
`Person of Ordinary Skill in the Art .................................................. 4
`D. Materials Considered ......................................................................... 5
`E.
`Legal Principles .................................................................................. 6
`SCIENTIFIC PRINCIPLES RELEVANT TO
`RADIOPHARMACEUTICALS ................................................................. 7
`A.
`Terminology Used in this Declaration .............................................. 7
`B.
`Radiopharmaceuticals ....................................................................... 9
`C. Common Components of Radiopharmaceuticals ......................... 12
`1.
`Targeting Moiety ..................................................................... 13
`2.
`Radiolabeling Moiety .............................................................. 15
`3.
`Linkers ..................................................................................... 18
`D. Radionuclides ................................................................................... 21
`E.
`Considerations Influencing the Development of
`Radiopharmaceuticals ..................................................................... 28
`1.
`Selectivity and Affinity of the Targeting Moiety ...................... 28
`2.
`Stability, Bioavailability and Other Factors Influence Design of
`Radiopharmaceuticals ............................................................. 30
`Requirements for Distributing Radiopharmaceuticals Can
`Influence Their Design ............................................................ 32
`Before 2017, There Was Significant Interest in Developing
`Radiopharmaceuticals that Selectively Targeted FAP for Therapy
`and Diagnosis of Cancer .................................................................. 37
`1.
`FAP Is Selectively Expressed by Many Types of Tumors ........ 37
`2.
`Skilled Artisans Were Actively Looking in the 2010’s for Small
`Molecules that Selectively Bound FAP to Use in
`Radiopharmaceuticals ............................................................. 40
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`F.
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`3.
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. ii
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`IPR2025-00808 Declaration of Brian Zeglis
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`2.
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`3.
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`4.
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`III. US-633, JANSEN AND MELETTA WOULD LEAD A SKILLED
`ARTISAN TO DEVELOP RADIOPHARMACEUTICALS BASED ON
`COMPOUND 60 OF JANSEN .................................................................. 44
`A. US-633 (EX1004) .............................................................................. 46
`1.
`US-633 Describes Low Molecular Weight
`Radiopharmaceuticals that Selectively Target FAP ................ 46
`US-633 Describes Construction of FAP-Targeting
`Radiopharmaceuticals ............................................................. 49
`US-633 Describes Using Known Radionuclides with FAP-
`Targeting Radiopharmaceuticals ............................................ 52
`US-633 Describes Chelators and Prosthetic Groups to Use in
`Radiopharmaceuticals ............................................................. 53
`a.
`Chelator Moieties .......................................................... 54
`b.
`Prosthetic Groups .......................................................... 59
`US-633 Describes Conjugating FAP-Binding Moieties to
`Imaging Agents Using Bi-Functionalized Linkers ................... 61
`US-633 Describes Examples of FAP-Targeting
`Radiopharmaceutical Compounds .......................................... 65
`B. Meletta (EX1008) ............................................................................. 69
`C.
`Jansen (EX1006) ............................................................................... 76
`1.
`Jansen Identifies the Need for Improved FAP-Targeting
`Moieties for Radiopharmaceuticals ......................................... 77
`Jansen Showcases Compound 60 as a Promising FAP
`Targeting Moiety ..................................................................... 81
`The Reported Properties of Compound 60 Make It an
`Appealing FAP-Targeting Moiety ........................................... 86
`D. A Skilled Artisan Would Have Considered the Collective
`Guidance in US-633, Meletta and Jansen to Design Novel FAP-
`Targeting Radiotracers ................................................................... 95
`A Skilled Artisan Would Have Selected a Radionuclide Based on
`the Imaging Platform to be Used .................................................... 98
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`E.
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`5.
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`6.
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`2.
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`3.
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. iii
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`F.
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`2.
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`3.
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`4.
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`2.
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`3.
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`G.
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`A Skilled Artisan Would Have Improved the FAP Radiotracers
`Illustrated in US-633 by Using Compound 60 as the Targeting
`Moiety .............................................................................................. 100
`Specific Radiotracers Containing Compound 60 and that Use a
`68Ga or 18F Radionuclide Would Have Been Obvious ................ 102
`1.
`A Skilled Artisan Would Have Attached a Linker-Radiolabeling
`Moiety at C6 or C7 of the Quinolinyl Ring of Compound 60 . 103
`A Skilled Artisan Would Have Used Well-Known Chelators
`Compatible with 68Ga or 99mTc .............................................. 112
`Examples of Radiotracers that Combine Compound 60 with
`Chelators and Radiometals ................................................... 113
`Examples of Radiotracers that Combine Compound 60 with
`Prosthetic Groups and Radiohalogens .................................. 119
`H. Compounds A1 to A4 Meet the Requirements of the Claims of the
`‘201 Patent ...................................................................................... 123
`1.
`Compounds A1 to A4 Contain the “B” (Radiolabel) and “L”
`(Linker) Components of the Claims ....................................... 124
`Compound 60 Meets the Requirements of the “A” (Targeting
`Moiety) Component of the Claims ......................................... 126
`Compounds A1 to A4 Meet the “Low Molecular Weight
`Compound” Requirement of the Claims ................................ 128
`A Skilled Artisan Would Have had a Reasonable Expectation of
`Successfully Developing a FAP-targeting Radiopharmaceutical
`Based on the Guidance of US-633, Jansen and Meletta ............. 133
`IV. US-121 AND JANSEN WOULD LEAD A SKILLED ARTISAN TO
`DEVELOP FAP-BASED RADIOPHARMACEUTICALS USING
`COMPOUND 60 OF JANSEN ................................................................ 135
`A. US-121 (EX1005) ............................................................................ 136
`1.
`US-121 Describes Low Molecular Weight Radiotracers for
`Targeting PSMA .................................................................... 136
`US-121 Highlights Benefits of PET Scanning with Radiotracers
`That Use 68Ga ........................................................................ 141
`US-121 Describes Conventional Chelators to Use in
`Radiotracers .......................................................................... 144
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. iv
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`I.
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`2.
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`3.
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`IPR2025-00808 Declaration of Brian Zeglis
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`4.
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`2.
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`US-121 Describes Linker Moieties Used to Assemble
`Radiotracers .......................................................................... 146
`Examples of Radiotracers Illustrated in US-121 ................... 148
`5.
`A Skilled Artisan Would Have Considered US-121 and Jansen
`Together Given their Common Focus on Targeting Cancer-
`Specific Biomarkers ....................................................................... 150
`C. A Skilled Artisan Would Have Designed a Low Molecular Weight
`FAP-Targeting Radiotracer Using the Particular Linker-Chelator
`Combinations in the Examples in US-121 with Jansen’s
`Compound 60 as the Targeting Moiety ........................................ 152
`1.
`A Skilled Artisan Would Have Selected Jansen Compound 60 as
`the Targeting Moiety for a FAP-based Radiotracer ............. 152
`A Skilled Artisan Would Have Viewed 68Ga or 99mTc as
`Appropriate Radionuclides to Use in the Radiotracers Being
`Described in US-121 ............................................................. 153
`D. A Skilled Artisan Would Have Replaced the Targeting Moiety in
`the Examples of Radiotracers Illustrated in US-121 with Jansen’s
`Compound 60 ................................................................................. 154
`Compounds B1 to B4 Meet the Requirements of the Claims of the
`‘201 Patent ...................................................................................... 162
`A Skilled Artisan Would Have Reasonably Expected the Modified
`Compounds Based on the US-121 Examples that Incorporate
`Compound 60 Would be Viable Radiotracers ............................. 165
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`B.
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`E.
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`F.
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. v
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`I.
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`Introduction
`A. Background and Qualifications
`1. My educational background, career history, and other relevant
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`qualifications are summarized below. I attach to this Declaration my curriculum
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`vitae, which provides a full and accurate description of my educational
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`background, professional experience, and qualifications (Appendix A).
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`2.
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`I received my Ph.D. in Chemistry from the California Institute of
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`Technology in 2009, where I studied the bioinorganic chemistry of DNA
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`mismatch-binding metal complexes under the guidance of Professor Jacqueline K.
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`Barton. I received a Bachelor of Science in Chemistry from Yale University in
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`2004, where I studied organometallic N-heterocyclic carbene complexes of
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`ruthenium and iridium under the tutelage of Professor Robert H. Crabtree. I
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`completed my postdoctoral work at Memorial Sloan Kettering Cancer Center in
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`2015, where I studied the design, synthesis, and in vivo validation of
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`radiopharmaceuticals for the nuclear imaging, theranostic imaging, and targeted
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`therapy of cancer under the auspices of Professor Jason S. Lewis.
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`3.
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`I currently serve as a Professor of Chemistry at Hunter College, City
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`University of New York. I have been a professor at Hunter College since 2015. I
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`began as an Assistant Professor in the Department of Chemistry from January 2015
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`through September 2019. I served as an Associate Professor in the same
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 1
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`IPR2025-00808 Declaration of Brian Zeglis
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`department from September 2019 to August 2022. Since August 2022, I have been
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`employed as a Full Professor in the Department of Chemistry.
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`4.
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`I have taught courses in Inorganic Chemistry and Inorganic Chemistry
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`Laboratory at Hunter College as recently as the 2023-2024 term. I also previously
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`taught an Introduction to Radiochemistry course as recently as Spring 2017.
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`5.
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`I have authored or co-authored 118 publications, largely in the field of
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`radiochemistry. I have published two textbooks on the subject of
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`radiopharmaceutical design and development, entitled “Radiopharmaceutical
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`Chemistry” (1st edition in 2019; 2nd edition coming in 2025) and
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`“Radiopharmaceutical Therapy” (published in 2023). I have also published several
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`book chapters in the field of radiopharmaceuticals for oncology applications. To
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`date, I have been invited to deliver 54 lectures at conferences, universities,
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`hospitals, and other institutions across the world.
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`6.
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`I am also a named inventor on three patents: U.S. Patent Nos.
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`7,786,298, 11,000,604, and 11,135,320. U.S. Patent Nos. 11,000,604 (entitled
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`“Reagent for Site-Selective Bioconjugation of Proteins or Antibodies”) and
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`11,135,320 (entitled “Radioligands for Pretargeted PET imaging and Methods of
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`their Therapeutic Use”) describe compounds and methods of radiolabeling
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`compounds for use in radiochemistry applications.
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 2
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`7.
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`I have received a number of awards in the field of nuclear medicine.
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`For example, in October 2022, I received the Roger Tsien Award for Excellence in
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`Chemical Biology from the World Molecular Imaging Society for my
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`contributions to the use of bioorthogonal chemistry to molecular imaging and
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`nuclear medicine.
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`8.
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`From 2020-2021 and since 2022, I have served as a Standing Member
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`of the National Institutes of Health Imaging Probes and Contrast Agents (IPCA)
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`Study Section.
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`9.
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`I currently serve as the Deputy Editor-in-Chief for the Molecular
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`Imaging and Biology scientific journal. I have served in this role since 2024.
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`Before that, I was an Associate Editor for the same journal from 2020-2024. Since
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`2016, I have also served on the Editorial Board of the Journal of Nuclear
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`Medicine. In addition, I have served as a reviewer for several journals in the past,
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`including Cancer Research, Clinical Cancer Research, Cancer Discovery,
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`Proceedings of the National Academy of Sciences, Chemical Communications,
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`Journal of the American Chemical Society, Journal of Nuclear Medicine, and
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`European Journal of Nuclear Medicine.
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`10. Since 2015, I have supervised 6 post-doctoral researchers, 16 graduate
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`students, and 15 undergraduate students in my laboratory.
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 3
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`B. Compensation
`11.
` I am being compensated for my time at the rate of $900 per hour for
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`my work in connection with this matter. I am being reimbursed for reasonable and
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`customary expenses associated with my work in this investigation. This
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`compensation is not dependent in any way on the contents of this Declaration, the
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`substance of any further opinions or testimony that I may provide, or the ultimate
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`outcome of this matter.
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`C.
`12.
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`Person of Ordinary Skill in the Art
` I understand that my analysis and opinions are to be provided using
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`the perspective of a person of ordinary skill in the art up to the date of October 23,
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`2017. I will refer to this period as the “2017 timeframe” in this Declaration.
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`13. The scientific field of the patent concerns radiopharmaceuticals, and
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`more particularly, radiopharmaceuticals designed for the nuclear imaging of cancer
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`cells. I am very familiar with this field, and the individuals who work within it,
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`including in the 2017 timeframe.
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`14.
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`I have been informed by counsel that a person of ordinary skill in the
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`art is a hypothetical person who is presumed to have the typical skills and
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`knowledge of someone working in the field of the invention. Based on my review
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`of the patent and my experience, I believe a person of ordinary skill in the art (who
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`I may refer to as “a skilled artisan”) would have had an undergraduate degree and a
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 4
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`IPR2025-00808 Declaration of Brian Zeglis
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`Ph.D. in chemistry, biochemistry, medicinal chemistry or a comparable field. The
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`person would have had experience with and/or knowledge of chemical synthesis
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`methods (e.g., organic synthesis, radiometal chelation and radiohalogen labeling of
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`prosthetic groups), assessment of cellular targets for radiopharmaceuticals, and
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`other techniques used in the design, development, testing and/or evaluation of
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`radiopharmaceuticals. The person would also be familiar with how
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`radiopharmaceuticals are distributed and used in patients to perform therapy or
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`nuclear imaging of diseases, including cancer.
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`15.
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`In the 2017 timeframe, I had at least the qualifications I outline above
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`for a person of ordinary skill in the art. The opinions I provide in this Declaration
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`are provided from the perspective of a person of ordinary skill in the art in the
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`2017 timeframe as I have described above.
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`16.
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`I understand that the disclosure of a patent consists of a narrative
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`section called the specification, which often includes drawings. I understand that a
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`patent ends with claims that define the invention.
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`D. Materials Considered
`17.
` My opinions are based on my years of education, research, and
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`experience, as well as my investigation and study of relevant materials. I reviewed
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`a number of publications in the course of my assessment, including those listed in
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 5
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`IPR2025-00808 Declaration of Brian Zeglis
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`Appendix A. I also relied on my extensive familiarity with the scientific literature
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`in this field.
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`E.
`18.
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`Legal Principles
`I am not a lawyer and am not offering opinions on the law. However,
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`I have been provided a general explanation of some of the legal requirements for
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`obtaining a patent.
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`19.
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`I have been informed that one requirement for patentability is that an
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`invention must not have been obvious to a person of ordinary skill in the art in
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`view of what was known in the prior art before the filling date of the patent. I also
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`have been informed that if a patent claim encompasses a compound that would
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`have been obvious in light of the prior art, that claim is unpatentable.
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`20.
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`I have been informed that for a claimed compound to be found
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`obvious, a person of ordinary skill in the art must have found a reason in the prior
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`art to make that compound and must have had a reasonable expectation of success
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`in achieving the claimed invention. I have been informed this does not require the
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`skilled artisan to have absolute certainty about achieving a desired result and that
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`an invention can be found obvious if a result is expected but still requires some
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`experimentation to confirm.
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`21.
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`I have been informed that if there is evidence that a particular
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`compound exhibits unexpected properties, enjoys significant commercial success,
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 6
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`IPR2025-00808 Declaration of Brian Zeglis
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`or meets a long-felt need, that evidence can support a finding that the compound is
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`not obvious. I have also been informed that for a claim defining a large class of
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`compounds, all of the members of the class must share the property or
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`characteristic to support a finding that the class of compounds is not obvious. I
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`have been informed that a claim defining a large class of compounds cannot
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`benefit from evidence showing only one or a few of the compounds within it
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`exhibits the particular unexpected property or characteristic associated with the
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`evidence. I also have been informed that to credit such evidence as supporting
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`non-obviousness, it must not be associated with a prior art feature of the claimed
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`invention.
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`II.
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`Scientific Principles Relevant to Radiopharmaceuticals
`22. The scientific field of the ’201 Patent concerns compounds used in
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`nuclear imaging or therapy, particularly those targeting FAP. The development of
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`radiopharmaceuticals, including those targeting FAP, was well-established in the
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`2017 timeframe. The explanations and observations I provide below reflect what a
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`person of ordinary skill in the art would have known as of October of 2017, and are
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`consistent with what that person would have believed as of that date.
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`A. Terminology Used in this Declaration
`23.
`I will use the following abbreviations and terminology in this
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`declaration:
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 7
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`(a)
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`“FAP” refers to the Fibroblast Activation Protein-α. FAP is
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`also referred to as “seprase.”1
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`(b)
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`(c)
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`(d)
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`“PSMA” refers to prostate-specific membrane antigen.
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`“PET” refers to Positron Emission Tomography.
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`“SPECT” refers to Single-Photon Emission Computed
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`Tomography.
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`(e)
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`“Radiopharmaceutical” is a chemical compound that contains a
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`radionuclide that is used for therapeutic or diagnostic purposes.
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`(f)
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`“Radiotracer” is a radiopharmaceutical that is used for nuclear
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`imaging purposes.
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`(g)
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`“Targeting moiety” refers to the portion of a
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`radiopharmaceutical that binds selectively to a cellular target
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`(e.g., FAP). This is also referred to as the “pharmacophore,”
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`the “warhead”, or comparable terms.
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`
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`1 EX1026 (Jia), 1 (“Fibroblast Activation Protein alpha (FAP-α) or seprase is an
`integral membrane serine peptidase.”); EX1004 (US-633), [0003] (“Seprase,
`also known as fibroblast activation protein alpha (FAP-α), is a transmembrane
`serine peptidase that belongs to the prolyl peptidase family.”).
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 8
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`IPR2025-00808 Declaration of Brian Zeglis
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`(h)
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`“Radiolabeling moiety” refers to the portion of a
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`radiopharmaceutical that is covalently linked to or non-
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`covalently complexed with a radionuclide. It may also be
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`referred to as an “imaging moiety.”
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`(i)
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`“Linker” refers to a portion of the radiopharmaceutical that
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`links the radiolabeling moiety to the targeting moiety. It may
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`also be referred to as a “tether,” “spacer,” or similar term.2
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`B. Radiopharmaceuticals
`24. Radiopharmaceuticals are specialized chemical compounds that
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`incorporate a radioactive form of an element (a radionuclide). When a dose of a
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`radiopharmaceutical is administered to a patient, the radiopharmaceutical bearing
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`the radionuclide migrates to and accumulates in targeted tissues.3 In therapeutic
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`applications, the radionuclide exerts a cytotoxic effect on the cells in which it has
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`accumulated. In diagnostic applications, the radionuclides emit radiation at the
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`location in the body where they have accumulated, which are then detected by a
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`
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`2 EX1009 (Jamous), 3881. See also EX1017 (Sarko), 2669.
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`3 EX1005 (US-121), [0175], [0183]-[0184]. See also EX1009 (Jamous), 3379-
`3380; EX1011 (Zeglis 2013), 1891; EX1018 (Fichna), 8-9.
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 9
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`device, such as a PET or SPECT scanner,4 to generate an image that can be
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`evaluated by a clinician.5
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`25. Radiopharmaceuticals are of particular interest in the clinical
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`diagnosis and treatment of cancers because tumors contain cells that have unique
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`characteristics that can be differentiated from cells in normal tissue and therefore
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`can be targeted for diagnostic and therapeutic purposes.6 As Jamous (EX1009)
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`explains:
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`Many tumors overexpress specific targets on the surface of their
`cells. The target ligands are used with radiolabels in cancer
`diagnosis and therapy in accordance with the key-lock principle.7
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`This “key-lock” principle ensures that the carrier molecule (the key) fits precisely
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`into the target receptor (the lock), allowing for high specificity in targeting tumor
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`cells.8
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`
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`4 EX1004 (US-633), [0005]. See also EX1010 (Zeglis 2011), 2; EX1009
`(Jamous), 3380-3381.
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`5 EX1004 (US-633), [0002], [0005], [0049]. See also EX1010 (Zeglis 2011), 2;
`EX1009 (Jamous), 3380-81.
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`6 EX1004 (US-633), [0005]. See also EX1010 (Zeglis 2011), 2.
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`7 EX1009 (Jamous), 3380.
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`8 EX1009 (Jamous), 3380.
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`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 10
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`26. Radiopharmaceuticals used in nuclear imaging are called
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`“radiotracers” or “tracers.” Radiotracers are given to patients at much lower doses
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`than radiopharmaceuticals given for therapeutic purposes. Due to the risks
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`associated with radiation exposure;9 the dose of a radiotracer is limited to the
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`minimum amount needed to produce emissions sufficient for imaging.10 As
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`Agdeppa (EX1027) explains:
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`Radiotracers are given at doses that do not elicit a pharmacologic
`event (orders of magnitude below therapeutic doses), are
`infrequently administered, and are designed to measure molecular
`processes, not modify the disease (97,98). These factors reduce the
`safety risks associated with radiotracers compared to therapeutics,
`yet they are regulated as though they carry the same risks. The
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`
`
`9 EX1037 (Karakatsanis), 528 (“However, radiation exposure can be a serious
`concern for adult and particularly children patients, especially in the case of
`PET/CT hybrid systems, due to the ionizing nature of both PET and CT
`radiation, with the latter contributing to relatively higher absorbed doses than
`the former modality.”).
`
`10 EX1037 (Karakatsanis), 528 (“By systematically and quantitatively
`analyzing…a range of dose levels, an accurate NECR-dosage response model
`can be designed allowing for the prediction of the minimum possible amount
`of dosage required to sufficiently maintain NECR, or statistically useful
`counts, at a quantitatively acceptable level.”).
`
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 11
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`

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`IPR2025-00808 Declaration of Brian Zeglis
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`reduced risks and different usage of imaging tracers support
`development of alternatives to the current regulatory process.11
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`C. Common Components of Radiopharmaceuticals
`27. Radiopharmaceuticals often employ a “modular” design with three
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`primary components:
`
`(a)
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`a targeting moiety that enables the radiopharmaceutical to
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`selectively bind to a biological target of interest;
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`(b)
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`a radiolabeling moiety that includes (i) a radionuclide and (ii) a
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`chemical moiety such as a chelator or prosthetic group that
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`forms a non-covalent complex with (chelator) or covalent bond
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`to (prosthetic group) the radionuclide; and
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`(c)
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`a linker (also called a “spacer” or a “tether”), which is a
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`chemical moiety that connects and positions the targeting and
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`radiolabeling moieties relative to each other to ensure that each
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`can carry out its respective function (i.e., binding to target or
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`delivery of radionuclide).
`
`
`
`11 EX1027 (Agdeppa), 293.
`
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 12
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`IPR2025-00808 Declaration of Brian Zeglis
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`28. An illustration of this modular, three-component radiopharmaceutical
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`design is shown below (with annotations).12 One benefit of the modular three-
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`component design is that it is flexible—it allows one to replace individual
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`components when designing, synthesizing and evaluating a new
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`radiopharmaceutical. I briefly discuss these common components below.
`
`Linker/spacer
`
`Targeting moiety (pharmacophore)
`
`Radionuclide
`
`Radiolabeling
`moiety
`
`EX1009, 3381 (Fig.1)(annotated)
`
`
`
`1.
`Targeting Moiety
`29. The “targeting moiety” in a radiopharmaceutical facilitates delivery of
`
`the radiopharmaceutical to a specific biological target within the body (e.g., a
`
`tumor, particular tissues, a particular organ).13 The targeting moiety is a
`
`
`
`12 EX1009 (Jamous), 3381 (Figure 1) (annotated).
`
`13 EX1009 (Jamous), 3381 (“There are numerous different carriers that have
`been designed and developed for the targeting of tumors. Several radiolabeled
`small molecules have been applied in vivo for PET imaging [].”).
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 13
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`

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`IPR2025-00808 Declaration of Brian Zeglis
`
`pharmacophore that binds selectively to a particular chemical structure that is
`
`present on cells within the biological target. The selective presence of the
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`chemical structure on the targeted cells but not on other cells in the body is
`
`important for ensuring that the radionuclide is delivered precisely to the biological
`
`target of interest.14 Selectivity can be achieved by the unique expression of the
`
`structure on target cells, or by a relatively higher level of expression of the
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`structure on target cells as compared to normal cells. The ability of the
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`radiopharmaceutical to bind selectively to target cells enhances the accuracy of
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`delivery of the radionuclide for both diagnostic and therapeutic
`
`radiopharmaceuticals while minimizing damage to normal tissues.
`
`30. Targeting moieties in a radiopharmaceutical can be small molecules,
`
`peptides, small proteins, and antibodies.15 As I wrote in 2011, small molecule PET
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`radiotracers have dominated the field of molecular imaging, as they can penetrate
`
`tissues quickly and have short half-lives in circulation.16 Small molecule
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`
`
`14 EX1009 (Jamous), 3381.
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`15 EX1009 (Jamous), 3380 (“They can be classified into three major
`categories…(a) radiolabeled monoclonal antibodies (b) receptor specific small
`proteins and peptides and (c) small molecules.”).
`
`16 EX1010 (Zeglis 2011), 1-3; EX1012 (Wadas), 2859. See also EX1020 (Saha),
`161.
`
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 14
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`

`

`IPR2025-00808 Declaration of Brian Zeglis
`
`radiotracers are also particularly useful in PET imaging because they are quickly
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`cleared from the patient’s body due to their rapid pharmacokinetic profiles.17 A
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`skilled artisan considering options for the targeting moiety of a
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`radiopharmaceutical intended for imaging of tumors would have certainly
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`considered small molecule candidates, given that many had been used previously
`
`in radiopharmaceuticals and due to the person’s extensive familiarity with the
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`design and production of such compounds.
`
`2.
`Radiolabeling Moiety
`31. A radiopharmaceutical must be capable of delivering the radionuclide
`
`to the target cells or tissues to enable non-invasive imaging or treatment of
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`pathological conditions.18 To do that, the radionuclide must be stably attached to
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`the radiopharmaceutical so that it does not dissociate before it reaches and
`
`accumulates within tissues containing the targeted cells.19
`
`
`
`17 EX1009 (Jamous), 3381.
`
`18 See, e.g., EX1004 (US-633), [0005], [0049]; EX1009 (Jamous), 3380-81 (the
`“reporting unit”); EX1010 (Zeglis 2011), 1-3; EX1013 (Price), 265-66
`(“kinetic inertness in vivo is ultimately the most crucial consideration.”).
`
`19 See, e.g., EX1009 (Jamous), 3385; EX1017 (Sarko), 2668; EX1018 (Fichna),
`5; EX1010 (Zeglis 2011), 3, 5-6.
`
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 15
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`

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`IPR2025-00808 Declaration of Brian Zeglis
`
`32. Radionuclides are incorporated in radiopharmaceuticals either by
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`stably coordinating the radionuclide within a chelator moiety or by covalently
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`linking the radionuclide to the radiopharmaceutical; both approaches have proven
`
`effective in ensuring that the radionuclide does not dissociate from the
`
`radiopharmaceutical.20 Chelators are used with radiometals (e.g., 68Ga, 99mTc) and
`
`form stable, coordination complexes with the radiometal. Covalent bonds are used
`
`to attach non-metallic radionuclides, particularly radiohalogens (e.g., 18F, 123I) to a
`
`prosthetic group. Chelators and prosthetic groups also must be capable of being
`
`covalently attached to the linker moiety of the radiopharmaceutical.
`
`33. Chelators are not “one-size-fits-all” propositions. Metallic cations can
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`have dramatically different chemical properties, and thus a chelator that
`
`coordinates one cation with high thermodynamic and kinetic stability may not be
`
`adequate for the sequestration of another. Put differently, the choice of radiometal
`
`largely dictates the choice of chelator.21 For example, smaller cationic radiometals,
`
`such as 68Ga and 64Cu, prefer to be coordinated by a mix of oxygen and nitrogen
`
`
`
`20 See, e.g., EX1017 (Sarko), 2668; EX1018 (Fichna), 5. See also EX1004 (US-
`633), [0048]; EX1010 (Zeglis 2011), 3.
`
`21 EX1011 (Zeglis 2013), 1884.
`
`Petitioner GE Healthcare Ltd.
`Ex., 1003, p. 16
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`IPR2025-00808 Declaration of Brian Zeglis
`
`donor atoms.22 Many widely used chelators for binding radiometals are
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`structurally related to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
`
`acid), which is known to bind tightly to cationic radiometals.23 There are many
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`known relatives of DOTA used for binding radiometals as part of a radiolabeling
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`moiety, such as NOTA, DOTAGA, and TETA.24 A skilled artisan would have been
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`familiar with chelators to use with different radiometals, as that topic has been
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`extensively addressed in the scientific literature.25
`
`34. Radiohalogens (e.g., 18F, 123I, 125I) are ordinarily attached to a
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`radiopharmaceutical via a coval